Arsonophenyl amino alcohols and the process of making the same



Patented Apr. 21, 1931 UNITED STATES PATENT OFFICE ROG-ER ADAMS AND CHARLES W. RODEWALD, OF URBANA, ILLINOIS, ASSIGNORS TO ABBOTT LABORATORIES, OF NORTH CHICAGO, ILLINOIS, A CORPORATION OF ILLINOIS ARSONOPIIENYL AMINO ALCOHOLS AND THE PROCESS OF MAKING THE SAME No Drawing.

Our invention relates to compounds of the general structure XHo As-aryl-NH-(CH OH,

where X represents hydrogen or a metallic element, aryl represents a benzene ring or a substituted benzene ring, and Y represents a numeral, 1 or greater than 1.

The objects of the invention are to produce a series of substances useful in the treatment of syphilis, and especially of the tertiary stage; to provide a series of intermediates from which said substances may be prepared, and to provide an improved process for producing substances of this general character.

One mole of an arsanilic acid or substituted arsanilic acid is dissolved in water containing an alkali, and one mole of w-halogen alkyl halogen carbonate (ZCOO(CH Z, where Z and Z are halogens, and Y is the numeral one or more) added in small portions with shaking. After the reaction is complete, the reaction mass is acidified, the solid filtered on, and recrystallized. This intermediate product which is a o-halogenalkyl arsonophenyl carbonate, is refluxed with an excess of alkali and acidified, whereupon the arsonophenyl amino alcohol precipitates; after filtration, it is obtained pure by recrystallization.

The intermediates m-halogen-alkyl-arsonophenyl carbonate) as well as the amino alcohols shrink when heated and then melt with decomposition. This property causes the melting point to vary by several degrees depending on the speed with which the substances are heated. The temperatures given in the experimental part are corrected.

The amino alcohols produced are dissolved in aqueous alkali in order to obtain solutions for use.

Speczfic compounds of the semes 1. p A rs 0 n 0 pheng Z cmz inoethaowl. -21.7 grams of p-arsa-nilic acid is dissolved in 200 c. c. of Water containing 4 grams of sodium hydroxide. 142 grams (1 mole) of ,B-chloroethyl chlorocarbonate is added in small portions with vigorous shaking, keeping the temperature below 35 C. A voluminous Application filed Gctober 10, 1923. Serial No. 667,618.

precipitate separates during the reaction. The shaking is continued for ten minutes after all the chloroethyl ehlorocarbonate has been added. Thirty c. c. of concentrated hydrochloric acid is added, the product filtered off and washed with water. After recrystallization from 30% acetic acid, the ,B-chloroethyl (p arsonophenyl) carbama te is obtained in the form of long needles which do not melt on heating to 250 C. 16 grams B-chloroethylp arsonophenyl) carbamate is refluxed for 1 hours with c c. of 20% sodium hydroxide and 50 c. c. of water. The solution is cooled and concentrated hydrochloric acid is added until it is barely acid to congo. The p-arsonophenyl-aminoethanol separates and is filtered off and crystallized from water. It melts with decomposition at about 171 173 G.

The above described reactions may be rep resented as follows:

1. (p) H O AsC H NI-I +CICOOCH CH CI 2. (D) H O ASC ILNI-ICOOCH CH Cl NaOH (p) II OyXSC I-LNCOOCH OH NaCl H 0 1.. 3. (p) H O AsC H NCOOCH CH:+2NaOH 5(1)) H O ASC ILNIICH CH OH+Na CO Equations 2 and 8 may be combined as follows:

(p) ngons-ofininnoooomcniclaemo 2. g? ArsonopimnyZ (main-0 )rogmnol.ychloro propyl- (p-arsonophenyl) -carbamate is prepared in a similar manner to that described for ,B-chloroethyl-p-arsonophenyl)- carbamate in Example 1.21.7 grams p-arsanilic acid is dissolved in a solution of 150 c. water and 20 c. c. of 20% sodium hydroxide. To the cooled solution, 15.? grams y-chloropropyl chlorocarbonate is added in v hydroxide and 100 c. c. of Water. The solution is cooled and hydrochloric acid added until congo red just turns violet. The desired p-arsonophenylamino-propanol separates in fine colorless platelets, which are illtered 01f and washed with water, then recrystallized from water. The product melts with decomposition at about 167 168 C.

The above described reactions may be represented as follows:

i. (p) ino aecanxn cicoocrncmcmcl aI{:OgASCgII NI'ICOOCI12CTI CICL CI nm 2. (p) I'I O AsC ILNHCOOCH CH CH CI+NaOH -i p n ogascun lx' coocri cmcm NaCl mo 3. (p) I'IaOsASC I'LFCOOCH Cll CH:+ZNHOH (p) n. .o -\sc iLNucmcmcmon M100:

3. o-Arsonophem l-aminoethanOZ 10.8 grams of o-arsanilic acid is dissolved in a solution of 100 c. c. of water and 10 c. c. of 20% sodium hydroxide solution. After cooling the solution to 20 (1., 7 grams of fl-chloro-ethyl-chloro-arbonate is added in small portions with vigorous shaking, keeping the temperature below 30 C. The product B-chloroethyl- (o-arsonophenyl) -carba mate separates as a dense white crystalline substance. The shaking is continued for a. few minutes after the linal addition of the chlorocarbonate. The solution made strongly acid to congo, the proi'lnct filtered off, washed with water and rcrrys'i'allizcd from water containing a little acetic a It melts with decomposition at about 15c": 157 C.

The o-arsonophenyl-aminoethanol is prepared by refluxing for 4; hours, 4.2 grams of ,B-chloroethyl- (o-arsonophenyl) -carl)a mate with 4.3 grams ((3 moles) oi? pot: "iuni hydroxide in 50 c. c. of water. The solution is cooled, made barely to congo with concentratml hydrochloric acid, and the product which precipitates out is recrystallized from water. It melts with decomposition at about 145 4413 (l.

y-chloro-propyl- (o-arsonophenyl) -carba mate is prepared by dissolving 10.8 grams of o-arsanilic acid in a solution of c. c. oi. water and 10 c. c. of 20% sodium hydroxide solution (1 mole) and after cooling to 20 7., 7.9 grams of -chloro propyl-chloroearbonate is added ant the reaction carried out as in Example 2 The crystals of -chloropropyl- (o-arsonophenyl) -carbamate are needleshaped and melt with decomposition at ahont 139140 C.

Two grams of the above product is refluxed for 4 hours with an excess of aqueous potassium hydroxide in ten percent solution. After cooling, hydrochloric acid is added until. the reaction is barely acid to congopaper, and the precipitated o-ars mophenylaminopropanol is filtered oil? and recrystallized from water. The colorless platelets melt with decomposition at about S%l85 C.

5. 111-50n0phenyl-t-met/lyl-3-am5n0othawOZ 23.1 grams of l-methyl, 3-aminophenylarsonic acid is dissolved in 200 c. c. of water containing 4 gran'is of sodium hydroxide. 14.2 grams of fichl0r0ethyl-chlorocarbonate is added in small portions with vigorous shaking, keeping the temperature below 30 C., and continuing the shaking for ten minutes after all the material has been added. The solution is made strongly acid to Congo, and the product filtered oil and washed with water. This product, 3-B-chloroethyl-(4- methyl, arsonophenyl)carbamate after recrystallization from water containing a little acetic acid, melts with decomposition at about lflsll95 C.

17 grams of 3-[3-chloroethyl-(4-metl1yl, arsonophenyl)-carbamate is refluxed for 4t hours with a solution oi 50 c. c. of 20% sodium hydroxide and 50 c. c. of water. After cooling the solution, it is made barely acid to congo with concentrated hydrochloric acid. The product which is thereby precipitated is arsonophenyl-d-methyl aminoethanol. It is filtered otf and recrystallized from water, from which it comes out in the form of white needles which melt with (lecomposition at about-144 145 C.

Having now described our invention, we claim:

1. As new products, the arsonophenyl amino alcohols of the general formula XI-IO As-ary1-NI-I (CH OII where X represents a hydrogen atom or a metallic element, aryl represents a benzene ring or substituted benzene ring, and Y is 1 or more than 1.

2. As new products the compounds of the general formula where X represents a hydrogen atom or a metallic element, and Y is 1 or more than 1.

3. As a new product, the compound bonate, acidifying and recrystallizing, treating with an alkali and then acidifying and recrystallizing.

5. The improved step in the art of producing ai'sonophenyl amino alcohols which consists in treating an arsanilic acid with an alkali and a w-halogen-alkyl halogen carbonate, acidifying and recrystallizing, refluxing with an alkali and then acidifying and recrystallizing.

6. As a new product, an aisanilic acid compound in which an amino hydrogen of an aisanilic acid is replaced by CH CH OH.

ROGER ADAMS. CHAS. W. RODEWVALD. 

